Prostate cancer is currently the most common cancer among American men. Regulation of prostatic cell growth is largely controlled by androgens including especially dihydrotestosterone (DHT). This compound is synthesized from the male hormone testosterone by the enzyme 5-alpha reductase which is encoded in the prostate by the SRD5A2 gene. The etiology of prostate cancer appears to include increased steroid 5-alpha reductase activity particularly across racial/ethnic groups which are at very different risk for prostate cancer, such as high-risk African-Americans and lower risk Asians, the two extreme groups for risk. We have identified and characterized genetic variability in the SRD5A2 gene among various racial/ethnic groups in the US and between prostate cancer cases and controls. These investigations made use of a large multiethnic cohort in Los Angeles and Hawaii. We propose to build on and expand our studies of the SRD5A2 gene and prostate cancer by epidemiologic, genetic and biochemical methods. It is our overall hypothesis that genetic variation at the SRD5A2 locus plays a significant role in predisposition to and progression of prostate cancer and in explaining the racial/ethnic variation of risk. To this end, we intend to investigate the following interrelated six specific aims: 1) To identify all constitutional ("germline") DNA variations across the entire SRD5A2 gene that might contribute to predisposition to prostate cancer; 2) To determine the relationship between each variant identified in Specific Aim 1 to prostate cancer risk in for racial/ethnic populations: 4) To identify somatic mutations in the SRD5A2 gene involved in prostate cancer progression; 5) To characterize the biochemical properties of the somatic DNA genetic variants identified in Specific aims 1 and 4 in an in vitro model system; 6) To determine the contribution of somatic DNA genetic variants in the SRD5A2 gene to prostate cancer progression within and across racial/ethnic groups. Therefore, we will investigate the molecular basis of predisposition to prostate cancer and its progression in a multidisciplinary study rooted in molecular epidemiology with significant implications for presymptomatic identification of at-risk individuals, targeted chemoprevention and improved treatment of this disease.